Lecture 4 – March 17, 2010

LIPIDS: LIPOPROTEINS/TRANSPORT
 
 General Features of Lipoproteins

 Apolipoproteins: specific lipid-binding proteins that attach to the surface

intracellular recognition for exocytosis of the nascent particle after synthesis
activation of lipid-processing enzymes in the bloodstream,
binding to cell surface receptors for endocytosis and clearance.

 Main lipid components: triacylglycerols, cholesterol esters, phospholipids.

 Major lipoproteins:
chylomicrons
very low density lipoproteins (VLDL)
low density lipoproteins (LDL)
high density lipoproteins (HDL)

 Subfraction: intermediate density lipoproteins (IDL)

 Electrophoretic mobility (charge):

HDLs =  lipoproteins
LDLs = -lipoproteins
VLDLs = pre- lipoproteins (intermediate between  and  mobility).
Figure 1. Model of low density lipoprotein. Other lipoproteins have a
similar structure differing in the core content of lipid and the type of
apoproteins on the surface of the molecule
 P
C
100%
P
P
80% C
P

60%
Composition
T C
40% C
T

20%
T T
0%
Chylo- VLDL LDL HDL
microns Lipoprotein Type
Figure 2. The major classes of lipoproteins and their relative content of
triacylglycerol (T), cholesterol (C) and protein (P).
 chylomicron interacts
Lymph system: with lipoprotein lipase
Chylomicrons Nascent chylo- removing FFA
to capillaries microns acquire
via lymph apo CII (C) and E non-hepatictissues
non-hepatic tissues
(E) from HDL
N

N
T
E
T

E
S
I

CE CE CE
CECE
CE CE
CECE

ApoB48 aids
with chylo-
micron
assembly

LIVER
Figure 3. Exogenous pathway of lipid transport.
Chylomicrons carry dietary fatty acids to tissues
and the remnants take cholesterol to the liver
 Triacylglycerol
in core Chylomicron (or VLDL)

To Liver Apo CII

Glycerol LIPOPROTEIN LIPASE

Free fatty acids Polysaccharide

Chain

Capillary Endothelial
Surface of cell
In cellulo (muscle & adipose)
Free fatty acids

Figure 4. Lipoprotein lipase action on chylomicron triacylglycerol (an

identical reaction occurs with VLDL)
 chylomicron interacts
with lipoprotein lipase
Lymph system: chylomicron removing FFA
acquires apo
CII (C) and E
(E) from HDL non-hepatictissues
non-hepatic tissues
N

N
T
E
T

E
S
I

CE CE CE
CECE
CE CE
CECE C E
E C
E
chylomicron E C
ApoB48 remnants lose EE E
CII to HDL

Liver: apo E receptor

takes up remnants to
deliver cholesterol

LIVER

Figure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty

acids to tissues and the remnants take cholesterol to the liver
 nascent VLDL acquires LPL hydrolyze TAGs; FFA
B100 (B) helps apo CII (C) and apo E uptake; LDL circulate to tissues
assemble and export (E) from HDL
nascent VLDL non-hepatictissues
non-hepatic tissues

LIVER
CE CE CE CE CE CE
CE C EC E B B
CE
CE

CII and E release to HDL B

bile acids
B
Cholesterol B
apo B100 on LDL bind B BB
uptake;
to receptor
excreted as B BB
bile acids LDL taken into the cell
Apo E binds to deliver cholesterol
liver receptor

HDL
scavenge
cholesterol
Figure 5. The liver-directed endogenous pathway
of lipoprotein metabolism.
 Chylomicrons: Fig. 6 Chylomicron Processing and Interface with HDL
Exogenous Pathway

Nascent Chylomicron B48

HDL: Both Pathways
Assembly in Gut Nascent HDL
Mediated by B48 E Assembled in liver
E A1 Loans apo E/ apo CII
CII
to nascent chylomicrons
E E & CII
B48 apo
E CII
from HDL
Mature Chylomicron E CII
Lipoprotein Lipase
Apo E and CII B48 capillary walls
added from HDL E hydrolyzes TAG
CII activates LPL CII deliver FFA into adipose/muscle

CII
CII
adipose &
FFA muscle Mature HDL
apo CII CE from peripheral cells via
Chylomicron Remnant A1
LCAT activated by apo A1
from mature chylomicron CII
Apo CII returned by
apo CII returned to HDL B48 CII CII chylomicrons
E

Triacylglycerol Cholesterol Phospholipid

ester
Fig. 6 VLDL/LDL Processing and Interface with HDL VLDL/LDL:
Endogenous Pathway
HDL: Both Pathways Nascent VLDL
Assembly in Liver
E B100 Mediated by B100
E
A1
CII E
apo CII & E
from HDL

E
CI B100
I

E
Mature VLDL
Lipoprotein Lipase Apo E and CII
CI
B100
capillary walls I E added from HDL
hydrolyzes TAG CII CII activates LPL
CII
deliver FFA into adipose/muscle
CII

adipose &
muscle FFA
Mature HDL
A1 E apo
CII
CII + E
Apo CII/E returned LDL
by VLDL E E from mature VLDL
CII
E
B100
CII
 Fig. 6 Clearance of Cholesterol by Liver from
Chylomicron Remnants, HDL and LDL

Chylomicron Mature LDL

A1
Remnant HDL
B100

A1
E
8
B4

8
B4

B100

E
E

E
8

A1
B4

E
E

B100

E E B100
Receptor Receptor receptor

CE Metabolism Bile acids

Figure 6. Consequence of Oxidized LDL Formation
LDL
Oxidation of LDL

Pathogenesis

Oxidized LDL

1. Uptake by "scavenger receptors" on

macrophages that invade artery walls;
become foam cells
2. Elicits CE deposition in artery walls
3. Atherosclerosis/CAD can develop
 sorting endosome:
LDL ligand/receptor transport vesicle-
receptor dissociation lysosome fuse forming
late endosome
Recycling
Recyclingofofreceptor
receptor lysosome
and clathrin

ooo
clathrin-
coated pit late endosome Golgi
NPC-1
ooo

mediated free pool of

ACEH transfer cholesterol ACAT (stimulated
CE  cholesterol
endocytosis B100  amino by cholesterol)
acids
CE stored in
vesicle
Cholesterol release for Cholesterol droplets
transport to liver Esterase CE CE
LDL
CE CERP Cholesterol metabolism to
bile acids or steroids
Membrane
Cholesterol Apo A1 receptor
A1
C
A
L

A1 E
Reverse
CII Cholesterol
CE in nascent HDL E
Transport
Figure 7. Cellular CII

cholesterol uptake, Apo A1 binds to receptor, activates

CERP to pump out cholesterol, and Mature HDL:
metabolism and release. LCAT to esterify cholesterol Cleared by liver
 Lipoprotein classes:
Lipo- Source Apo Protein:Lipid/ Function
protein Proteins in Major (minor) Lipid
Mature Transported
Chylo- gut B48, CII*, 1:49 Dietary:
microns E* triacylglycerol (CE) FFA  Adipose/muscle
CE  Liver via remnants
VLDL liver B100, 1:9 Synthesized:
CII*, E* triacylglycerol (CE) FFA adipose/muscle
CE  LDL
LDL blood B100 1:3 CE to liver (70%) and
cholesterol ester peripheral cells (30%)
HDL liver A1, CII, E 1:1 supplies apo CII, E to
("ACE") cholesterol ester chylomicrons and VLDL;
mediates reverse
cholesterol transport
 Functions of Apolipoproteins & Enzymes in Lipid Transport/Processing

Protein Site of Action Activator Function

(Enzyme)
excises FFA from TAGs in chylomicrons and
LPL (Enzyme) capillary walls apo CII
VLDLs for adipose and muscle
ACAT (Enzyme) inside cells free choles cholesterol ester storage
cholesterol extraction from cells  HDL carries
LCAT (Enzyme) blood apo A1
CE for liver clearance (to bile acids)
apo A1
plasma flips cholesterol (and lecithin) to outer layer of
CERP (choles.
membrane lipid bilayer for LCAT action in blood
Induced)
intestine/liver
TTP none loads TAGs onto B48 (gut) and B100 (liver)
smooth ER
blood, plasma activates LCAT and CERP; binds to apo A1
Apo A1 none
membrane receptors on cells requiring cholesterol extraction
Apo B48 Gut none export of chylomicrons from intestinal cells
Apo B100 Various cells none ligand for LDL receptor; export of liver VLDL
Apo CII capillary walls none activates lipoprotein lipase
Apo E liver none receptor ligand - clears remnants, IDL, and HDL